Matrix metalloproteases (xe2x80x9cMMPsxe2x80x9d) are a family of proteases (enzymes) involved in the degradation and remodeling of connective tissues. Members of this family of endopeptidase enzymes are secreted as proenzymes from various cell types that reside in or are associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells, and invasive or metastatic tumor cells. MMP expression is stimulated by growth factors and cytokines in the local tissue environment, where these enzymes act to specifically degrade protein components of the extracellular matrix, such as collagen, proteoglycans (protein core), fibronectin and laminin. These ubiquitous extracellular matrix components are present in the linings of joints, interstitial connective tissues, basement membranes and cartilage.
The MMPs share a number of properties, including zinc and calcium dependence, secretion as zymogens, and 40-50% amino acid sequence homology. Eleven metalloenzymes have been well-characterized as MMP""s in humans, including three collagenases, three stromelysins, two gelatinases, matrilysin, metalloelastase, and membrane-type MMP, as discussed in greater detail below.
Interstitial collagenases catalyze the initial and rate-limiting cleavage of native collagen types I, II and III. Collagen, the major structural protein of mammals, is an essential component of the matrix of many tissues, for example, cartilage, bone, tendon and skin. Interstitial collagenases are very specific matrix metalloproteases which cleave these collagens to give two fragments which spontaneously denature at physiological temperatures and therefore become susceptible to cleavage by less specific enzymes. Cleavage by the collagenases results in the loss of structural integrity of the target tissue, essentially an irreversible process. There are currently three known human collagenases, the first two of which are relatively well-characterized (FASEB J., 5, 2145-54 (1991)). Human fibroblast-type collagenase (HFC, MMP-1, or collagenase-1) is produced by a wide variety of cells including fibroblasts and macrophages. Human neutrophil-type collagenase (HNC, MMP-8, or collagenase-2) has so far only been demonstrated to be produced by neutrophils. The most recently discovered member of this group of MMPs is human collagenase-3 (MMP-13), which was originally found in breast carcinomas (J. Biol. Chem., 269, 16,766-16,773) (1994)), but has since shown to be produced by chondrocytes (J. Clin. Invest., 97, 761-768, 1996).
The gelatinases include two distinct, but highly related, enzymes: a 72-kD enzyme (gelatinase A, HFG, MMP-2) secreted by fibroblasts and a wide variety of other cell types, and a 92-kD enzyme (gelatinase B, HNG, MMP-9) released by mononuclear phagocytes, neutrophils, corneal epithelial cells, tumor cells, cytotrophoblasts and keratinocytes. These gelatinases have been shown to degrade gelatins (denatured collagens), collagen types IV (basement membrane) and V, fibronectin and insoluble elastin.
Stromelysins 1 and 2 have been shown to cleave a broad range of matrix substrates, including laminin, fibronectin, proteoglycans, and collagen types IV and IX in their non-helical domains.
Matrilysin (MMP-7, PUMP-1) has been shown to degrade a wide range of matrix substrates including proteoglycans, gelatins, fibronectin, elastin and laminin. Its expression has been documented in mononuclear phagocytes, rate uterine explants and sporadically in tumors. Other less characterized MMPs include macrophage metalloelastase (MME, MMP-12), membrane type MMP (MMP-14), and stromelysin-3 (MMP-11).
Excessive degradation of extracellular matrix by MMPs is implicated in the pathogenesis of many diseases of both chronic and acute nature. For example, numerous studies, as reviewed in Exp. Opin. Invest. Drugs, 5, 323-335, (1996), have established that expression and activation of MMPs are critical events in tumor growth, invasion and metastasis. In addition, MMP activity has been found to be required for angiogenesis, which is necessary for tumor growth as well for other pathological conditions such as macular degeneration.
MMPs, especially stromelysin-1, collagenases-1, and collagenase-3, have been strongly implicated in the destruction of articular cartilage that is the hallmark of rheumatoid arthritis and osteoarthritis. See, for example, J. Clin. Invest., 97,761-768 (1996). In addition, the tissue destruction associated with gingivitis and periodontal disease is believed to be mediated by overexpression of MMPs in response to proinflammatory cytokines. See Molecular Pathogenesis of Periodontal Disease, Ch. 17, 191-202 (1994). Other diseases in which critical roles for MMPs have been identified include multiple sclerosis (J. Neuroimmunol., 41, 29-34 (1992)), corneal ulceration (Invest. Opthalmol and Visual Sci., 32, 1569-1575 (1989)), stroke (Brain Research, 703, 151-155 (1995) and J. Cereb. Blood Flow Metab., 16, 360-366 (1996)), sun-induced skin ageing (Nature, 379, 335-339 (1996)), chronic obstructive pulmonary disease, such as emphysema (Am. J. Respir. Cell. Mol. Biol. 7, 5160-5165 (1994)), chronic ulceration (J. Clin. Invest., 94, 79-88 (1994)), cardiac arrhythmia, and endometriosis. Finally, roles for MMP-mediated degradation of basement membranes have been proposed in the rupture of atherosclerotic plaques (Basic Res. Cardiol., 89(SUPPL.1), 59-70, (1994)) and in the development of glomerular disease (J. Clin. Invest., 97, 1094-1101 (1996)).
Inhibitors of MMPs are expected to provide useful treatments for the diseases described above in which degradation of the extracellular matrix by MMPs contributes to the pathogenesis of the disease. In general, selective MMP inhibitors of particular subsets of MMPs may offer therapeutic advantages, as it has been typically observed that a limited number of members of the MMP family are involved in any one of the disease states listed above. For example, the involvement of individual collagenases in the degradation of tissue collagens probably depends markedly on the tissue. The tissue distribution of human collagenases suggests that collagenase-3 is the major participant in the degradation of the collagen matrix of cartilage, while collagenase-1 is more likely to be involved in tissue remodeling of skin and other soft tissues. In addition, stromelysin-1 appears to be largely responsible for excessive loss of proteoglycan from cartilage. Thus, the inventive compounds disclosed herein that are selective inhibitors for collagenase-3 and stromelysin over collagenase-1 are preferred for treatment of diseases associated with cartilage erosion, such as rheumatoid and osteoarthritis. Similarly, among the MMPs, metalloelastase has been specifically implicated in the pathology of pulmonary emphysema. See J. Biol. Chem. 270, 14568-14575 (1995).
The design and uses of MMP inhibitors are reviewed, for example, in J. Enzyme Inhibition, 2, 1-22 (1987); Progress in Medicinal Chemistry 29, 271-334 (1992); Current Medicinal Chemistry, 2, 743-762 (1995); Exp. Opin. Ther. Patents, 5, 1287-1296 (1995); and Drug Discovery Today, 1, 16-26 (1996). MMP inhibitors are also the subject of numerous patents and patent applications. In the majority of these publications, the preferred inventive compounds are hydroxamic acids, as it has been well-established that the hydroxamate function is the optimal zinc-coordinating functionality for binding to the active site of MMPs. For example, the hydroxamate inhibitors described in the literature are generally 100 to 1000-fold more potent than the correponding inhibitors wherein the hydroxamic acid functionality is replaced by a carboxylic acid functionality. Nevertheless, hydroxamic acids tend to exhibit relatively poor bioavailability. The preferred compounds disclosed herein are carboxylic acid inhibitors that possess inhibitory potency against certain of the MMPs that is comparable to the potency of the hydroxamic acid inhibitors that have been reported in the literature. The following patents and patent applications disclose carboxylic acid inhibitiors that are, as are the inventive carboxylic acid inhibitors disclosed herein, monoamine derivatives of substituted succinic acids: Celltech Ltd.: EP-A-0489577 (WO 92/099565), EP-A-0489579, WO 93/24475, WO 93/244449; British Biotech Pharameuticals Ltd.: WO 95/32944, WO 95/19961; Sterling Winthrop, Inc.: U.S. Pat. No. 5,256,657; Sanofi Winthrop, Inc.: WO 95/22966; and Syntex (U.S.A.) Inc. WO 94/04735, WO 95/12603, and WO 96/16027.
The present invention is directed to compounds of the formula I: 
wherein
X is a single bond or a straight or branched, saturated or unsaturated chain containing 1 to 6 carbon atoms, wherein one or more of the carbon atoms are optionally independently replaced with O or S, and wherein one or more of the hydrogen atoms are optionally replaced with F;
Y is a single bond, xe2x80x94CH(OH)xe2x80x94, or xe2x80x94C(O)xe2x80x94;
R1 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group;
R2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C(O)R10 
wherein R10 is H, an O-alkyl group, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NR11R12;
wherein R11 is H, an alkyl group, an O-alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and wherein R12 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or wherein R11 and R12 form, together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group; and
R3 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, NR11R12, or OR11, wherein R11 and R12 are as defined above,
or R2 and R3, together with the atom(s) to which they are attached, form a cycloalkyl group or a heterocycloalkyl group;
R4 is H or any suitable organic moiety;
R5 is C(O)NHOH, C(O)OR13, SH, N(OH)CHO, SC(O)R14, P(O)(OH)R15, or P(O)(OH)OR13;
R13 is H, an alkyl group, or an aryl group,
R14 is an alkyl group or an aryl group, and
R15 is an alkyl group; and 
xe2x80x83is a heteroaryl group having five ring atoms, including 1, 2 or 3 heteroatoms selected from O, S, and N;
and pharmaceutically acceptable salts and solvates thereof, and pharmaceutically acceptable prodrugs thereof, said prodrugs being different from compounds of the formula (I); with the proviso that if the compound of formula (I) is: 
wherein R1, R4, and R5 are as defined above, W is H, OH, a halo group, an alkyl group, or an O-alkyl group, and further wherein
when m is 2, 3, or 4, n is 1, 2, 3, or 4, and A is CH2, O, NH, or N-alkyl; and
when m is 4, 5, or 6, n is 0, and A is xe2x80x94CHJxe2x80x94, wherein J is carboxy, alkoxycarbonyl, or carbamoyl;
or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound of the formula (I); then 
is pyrrolyl.
The present invention is further directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound of the formula (I).
The present invention is even further directed to methods of using the the compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, and pharmaceutically acceptable prodrugs thereof, said prodrug being different from a compound of the formula (I).
The present invention is directed to compounds of the formula I: 
wherein
X is a single bond or a straight or branched, saturated or unsaturated chain containing 1 to 6 carbon atoms, wherein one or more of the carbon atoms are optionally independently replaced with O or S, and wherein one or more of the hydrogen atoms are optionally replaced with F;
Y is a single bond, xe2x80x94CH(OH)xe2x80x94, or xe2x80x94C(O)xe2x80x94;
R1 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group;
R2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C(O)R10,
wherein R10 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NR11R12;
wherein R11 is H, an alkyl group, an O-alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and
wherein R12 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group,
or wherein R11 and R12 form, together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group; and
R3 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, NR11R12, or OR11, wherein R11 and R12 are as defined above,
or R2 and R3, together with the atom(s) to which they are attached, form a cycloalkyl group or a heterocycloalkyl group;
R4 is H or any suitable organic moiety;
R5 is C(O)NHOH, C(O)OR13, SH, N(OH)CHO, SC(O)R14, P(O)(OH)R15, or P(O)(OH)OR13,
wherein R13 is H, an alkyl group, or an aryl group;
R14 is an alkyl group or an aryl group; and
R15 is an alkyl group; and 
xe2x80x83is a heteroaryl group having five ring atoms, including 1, 2 or 3 heteroatoms selected from O, S, and N;
and pharmaceutically acceptable salts and solvates thereof, and pharmaceutically acceptable prodrugs thereof, said prodrugs being different from compounds of the formula (I); with the proviso that if the compound of formula (I) is: 
wherein R1, R4, and R5 are as defined above, W is H, OH, a halo group, an alkyl group, or an O-alkyl group, and further wherein
when m is 2, 3, or 4, n is 1, 2, 3, or 4, and A is CH2, O, NH, or N-alkyl; or
when m is 4, 5, or 6, n is 0, and A is xe2x80x94CHJxe2x80x94, wherein J is carboxy, alkoxycarbonyl, or carbamoyl;
or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound of the formula (I), said prodrug being different from a compound of the formula (I); then 
is pyrrolyl.
More preferably the compounds of the present invention are selected from compounds of the formula I wherein
X is a single bond;
Y is a single bond, xe2x80x94CH(OH)xe2x80x94 or xe2x80x94C(O)xe2x80x94;
R1 is an aryl group or a heteroaryl group;
R2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C(O)R10, wherein R10 is as defined above;
R3 is H, an alkyl group, a heteroaryl group, NR11R12 or OR11, wherein R11 and R12 are as defined above
or R2 and R3, together with the atoms to which they are attached, form a cycloalkyl group or heterocycloalkyl group;
R4 is H, an alkyl group, OH, an O-alkyl group, NH2, NH-alkyl, or a cycloalkyl group;
R5 is C(O)NHOH, C(O)OR13, SH, or SC(O)R14,
wherein R13 is H, an alkyl group, or an aryl group, and R14 is an alkyl group or an aryl group; and 
xe2x80x83is pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or triazolyl;
or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound of the formula (I).
In the compounds of the present invention, and the pharmaceutically acceptable salts and solvates thereof, and pharmaceutically acceptable prodrugs thereof, preferably X is a single bond.
In particularly preferred embodiments, when Y is xe2x80x94CH(OH)xe2x80x94, preferably R3 is H or an alkyl group or together with R2 and the atom(s) to which R2 and R3 are attached forms a cycloalkyl group or heterocycloalkyl group, and more preferably R3 is H. When Y is xe2x80x94C(O)xe2x80x94, preferably R3 is an alkyl group, NR11R12, or OR11, wherein R11 and R12 are as defined above, or together with R2 and the atoms to which R3 and R2 are attached, forms a cycloalkyl group or heterocycloalkyl group. When Y is a single bond, preferably R3 is a heteroaryl group, more preferably the heteroaryl group: 
wherein R21 and R22 are independently any suitable organic moiety or together with the carbon atoms to which they are attached form an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group. Preferably R21 and R22 are selected from hydrogen, an alkyl group, an aryl group, a heteroaryl group, a halo group, a C(O)O-alkyl group, a carbamoyl group, a cycloalkyl group, or a heterocycloalkyl group.
Preferably R1 is an aryl group or a heteroaryl group. More preferably R1 is an aryl group of the formula: 
wherein Z is H, halogen, an alkyl group, an O-alkyl group, a cyano group, a hydroxy group, an aryl group, a heteroaryl group, or a heterocycloalkyl group.
Preferably R4 is H, an alkyl group, or OH. More preferably R4 is H or an alkyl group selected from CHR16OH and CH(NHR17)R16, wherein R16 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and R17 is C(O)R18, SOR18, H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or R16 and R17, together with the atoms to which they are attached, form a heterocycloalkyl group; wherein R18 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NR19R20; wherein R19 and R20 independently are H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or R19 and R20, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group.
Preferably 
is pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or triazolyl, more preferably is pyrrolyl, fuyl or thienyl, and most preferably is pyrrolyl.
Preferably R5 is C(O)NHOH or C(O)OR13, wherein R13 is hydrogen.
Particularly preferred compounds according to the invention include:
N-[2,2-Dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic Acid;
N-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17]octadeca-11(18),12,14,16-tetraen-9(S)-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic Acid;
N-[2,2-Dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-[3-(pyridin-4-yl)-1H-pyrrol-1-yl]succinamic Acid;
3(R)-[3-(Biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic Acid;
3(R)-[3-(Biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1 (S)-[(1H-imidazol-4-yl)methyl]ethyl]succinamic Acid;
N-[2,2-Dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-[3-(4-propylphenyl)-1H-pyrrol-1-yl]succinamic Acid;
3 (R)-[3-(4-Cyanophenyl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic Acid;
N-[2,2-Dimethyl-1(S)-(hydroxymethyl)propyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic Acid;
N-(2-Hydroxy-1(S)-phenylethyl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic Acid;
3(R)-[3-(4xe2x80x2-Cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic Acid;
3(R)-[3-(4xe2x80x2-Cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)-propyl]succinamic Acid;
3(R)-[3-(4xe2x80x2-Carbarmoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic Acid;
3(R)-[3-(4xe2x80x2-Carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2 dimethyl-1(S)-(pyridin-4-yl-carbamoyl)propyl]succinamic Acid;
3(R)-[3-(4xe2x80x2-Cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(hydroxymethyl)propyl]succinamic Acid;
N-(2(R)-Hydroxyindan-1(R)-yl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic Acid;
N-(2,2-Dimethyl-1(S)-(methylcarbamoyl)propyl)-3(R)-[3-(4-(pyridin-4-yl)phenyl)-1H-pyrrol-1-yl]succinamic Acid;
N-(4,4-Dimethyl-2-oxo-tetrahydrofuran-3(S)-yl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic Acid;
N-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6. 1.012,7]octadeca-11(18),12,14,16-tetraen-9(S)-yl-(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic Acid;
N-[2,2-Dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic Acid;
N-[1(S)-(1H-Imidazol-2-yl)-3-methylbutyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic Acid;
N1-[2,2-Dimethyl-1(S)-(hydroxymethyl)propyl]-N4-hydroxy-2(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic;
N-[2,2-Dimethyl-1(S)-(methylcarbamoyl)propyl]-3(S)-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]succinamic Acid;
3(S)-[1-(4xe2x80x2-Cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic Acid;
3(S)-[1-(4xe2x80x2-Cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]succinamic Acid;
3(S)-[1-(4xe2x80x2-Cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(4,4-dimethyl-2-oxo-tetrahydrofuran-3(S)-yl)succinamic Acid;
3(R)-[3-(4xe2x80x2-Cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]succinamic Acid;
3(R)-[3-(4-Cyanophenyl)-1H-pyrrol-1-yl]-N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]succinamic Acid;
N-[2,2-Dimethyl-1(S)-(hydroxymethyl)propyl]-3(S)-[1-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-3-yl]succinamic Acid;
3(R)-{3-[2-(4-Cyanophenyl)ethynyl]-1H-pyrrol-1-yl}-N-[2,2-dimethyl-1(S)(methylcarbamoyl)-propyl]succinamic Acid;
3(R)-{3-[2-(4-Cyanophenyl)ethyl]-1H-pyrrol-1-yl}-N-[2,2-dimethyl-1(S)(methylcarbamoyl)-propyl]succinamic Acid;
N1-Hydroxy-N4-methyl-3(R)-[3-(4-(pyridin-4-yl)phenyl)-1H-pyrrol-1-yl]succinamide;
3(R)-[3-(4xe2x80x2-Cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]-2(S)-cyclopropyl-N-(2,2-dimethyl-1(S)(methylcarbamoyl)propyl)succinamic Acid;
3(S)-[2-(4xe2x80x2-Cyanobiphenyl-4-yl)furan-4-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic Acid;
3(S)-[1-(4xe2x80x2-Cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)-2(R)-(hydroxymethyl)succinamic Acid;
3(S)-[1-(4xe2x80x2-Cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)-2(S)-(hydroxy)succinamic Acid;
3(R)-[3-(4xe2x80x2-Cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)-2(S)-(hydroxy)succinamic Acid;
and the pharmaceutically acceptable salts and solvates thereof, and the pharmaceutically acceptable prodrugs thereof.
As used in the present application, the following definitions apply:
An xe2x80x9calkyl groupxe2x80x9d is intended to mean a straight or branched chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl, and the like, which may be unsubstituted (i.e., containing only carbon and hydrogen) or substituted by one or more suitable substituents as defined below.
An xe2x80x9cO-alkyl groupxe2x80x9d is intended to mean an oxygen bonded to an alkyl group, wherein the alkyl group is as defined above.
A xe2x80x9ccycloalkyl groupxe2x80x9d is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon ring atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1.]heptyl, bicyclo[2.2.1.]hept-2-en-5-yl, bicyclo[2.2.2]octyl, bicyclo[3.2.1.]nonyl, bicyclo[4.3.0]nonyl bicyclo[4.4.0]decyl, indan-1-yl, indan-2-yl, tetralin-1-yl, tetralin-2-yl, adamantyl, and the like.
A xe2x80x9cheterocycloalkyl groupxe2x80x9d is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, and which includes 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the radical is unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like.
An xe2x80x9caryl groupxe2x80x9d is intended to mean an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluoren-2-yl, indan-5-yl, and the like.
A xe2x80x9cheteroaryl groupxe2x80x9d is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, benzofuryl, isobenzofuryl, benzothienyl, quinolyl, isoquinolyl, phthalazinyl, carbazolyl, purinyl, pteridinyl, acridinyl, phenanthrolinyl, phenoxazinyl, phenothiazinyl, and the like.
An xe2x80x9cacyl groupxe2x80x9d is intended to mean a xe2x80x94C(O)xe2x80x94Rxe2x80x94 radical, wherein R is any suitable substituent as defined below.
A xe2x80x9csulfonyl groupxe2x80x9d is intended to mean a xe2x80x94S(O)(O)xe2x80x94Rxe2x80x94 radical, wherein R is any suitable substituent as defined below.
The term xe2x80x9csuitable substituentxe2x80x9d is intended to mean any of the substituents recognizable to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable substituents include, but are not limited to, oxo groups, alkyl groups, hydroxy groups, halo groups, cyano groups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, trialkylsilyl groups,
groups of formula (A) 
wherein Ra is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group,
groups of formula (B) 
wherein Ra is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group,
groups of formula (C) 
wherein Rb and Rc are independently hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, and aryl group, or a heteroaryl group,
groups of formula (D) 
wherein Rd is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, or an acylamino group; and Rc is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an amino group, an alkylamino group, or a dialkylamino group,
groups of formula (E) 
wherein Rf is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group,
groups of formula (F) 
wherein Rg and Rh are independently hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group,
groups of formula (G) 
wherein Ri is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula (A), formula (B), formula (C), formula (H), or formula (K),
groups of formula (H) 
wherein Rj is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, or a group of formula (A), formula (B), formula (C) or formula (D); and wherein Rk is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula (A), formula (B), formula (C), formula (D), formula (E), or formula (F),
groups of formula (J) 
wherein Rl is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group formula (C), and
groups of formula (K) 
wherein Rm and Rn are independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, and alkoxy group, an amino group, an alkylamino group, or a dialkylamino group.
The term xe2x80x9csuitable organic moietyxe2x80x9d is intended to mean any organic moiety recognizable to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable organic moieties include, but are not limited to oxo groups, alkyl groups, hydroxy groups, halo groups, cyano groups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, trialkylsilyl groups, and groups of formulas (A), (B), (C), (D), (E), (F), (G), (H), (J), and (K), as defined above.
A xe2x80x9chydroxy groupxe2x80x9d is intended to mean the radical xe2x80x94OH.
An xe2x80x9coxo groupxe2x80x9d is intended to mean the divalent radical xe2x95x90O.
A xe2x80x9chalo groupxe2x80x9d is intended to mean any of the radicals xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I.
A xe2x80x9ccyano groupxe2x80x9d is intended to mean the radical xe2x80x94Cxe2x89xa1N.
A xe2x80x9cnitro groupxe2x80x9d is intended to mean the radical xe2x80x94NO2.
A xe2x80x9ctrialkylsilyl groupxe2x80x9d is intended to mean the radical xe2x80x94SiRpRqRs, where Rp, Rq, and Rs are each independently an alkyl group.
A xe2x80x9ccarboxy groupxe2x80x9d is intended to mean a group of formula (B) wherein Rt is hydrogen.
A xe2x80x9calkoxycarbonyl groupxe2x80x9d is intended to mean a group of formula (B) wherein Rt is an alkyl group as defined above.
A xe2x80x9ccarbamoyl groupxe2x80x9d is intended to mean a group of formula (C) wherein Rt and Rt are both hydrogen.
An xe2x80x9camino groupxe2x80x9d is intended to mean the radical xe2x80x94NH2.
An xe2x80x9calkylamino groupxe2x80x9d is intended to mean the radical xe2x80x94NHRu, wherein Ru is an alkyl group as defined above.
A xe2x80x9cdialkylamino groupxe2x80x9d is intended to mean the radical xe2x80x94NRuRv, wherein Ru and Rv, which are the same or different, are each an alkyl group as defined above.
A xe2x80x9cpharmaceutically acceptable prodrugxe2x80x9d is intended to mean a compound that may converted under physiological conditions or by solvolysis to a compound of the formula I.
A xe2x80x9cpharmaceutically acceptable solvatexe2x80x9d is intended to mean a solvate that retains the biological effectiveness and properties of the biologically active components of compounds of formula I.
Examples of pharmaceutically acceptable solvates include, but are not limited to, compounds of formula I in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
In the case of solid formulations, it is understood that the inventive compounds may exist in different forms, such as stable and metastable crystalline forms and isotropic and amorphous forms, all of which are intended to be within the scope of the present invention.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to mean those salts that retain the biological effectiveness and properties of the free acids and bases and that are not biologically or otherwise undesirable.
Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxyenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, xcex3-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
If the inventive compound is a base, the desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such as glucuronic acid and galacturonic acid, alpha-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such a p-toluenesulfonic acid or ethanesulfonic acid, or the like.
If the inventive compound is an acid, the desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal or alkaline earth metal hydroxide or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
The inventive compounds may exist as single stereoisomers, racemates and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Preferably, the compounds of the present invention are used in a form that contains at least 90% of a single isomer (80% enantiomeric or diastereomeric excess), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.). Compounds identified herein as single stereoisomers are meant to describe compounds used in a form that contains at least 90% of a single isomer.
The present invention is further directed to methods of inhibiting matrix metalloproteinase activity that comprise contacting the protease with an effective amount of a compound of formula I or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt or solvate thereof. For example, one can inhibit matrix metalloproteinase activity in mammalian tissue by administering a compound of formula I or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt or solvate thereof. The activity of the inventive compounds as inhibitors of matrix metalloproteinase activity may be measured by any of the methods available to those skilled in the art, including in vivo and in vitro assays. Examples of suitable assays for activity measurements include the fluorometric determination of the hydrolysis rate of a fluorescently-labelled peptide substrate, which is described herein.
Administration of the compounds of the formula I, or their pharmaceutically acceptable prodrugs or pharmaceutically acceptable salts or solvates, may be performed according to any of the accepted modes of administration available to those skilled in the art. Illustrative examples of suitable modes of administration include, but are not limited to, oral, nasal, intraocular, parenteral, topical, transdermal and rectal.
The inventive compounds of formula I, and their pharmaceutically acceptable prodrugs and pharmaceutically acceptable salts and solvates, may be administered as a pharmaceutical composition in any suitable pharmaceutical form recognizable to the skilled artisan. Suitable pharmaceutical forms include, but are not limited to, solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions and aerosols. The pharmaceutical composition may also include suitable excipients, diluents, vehicles and carriers, as well as other pharmaceutically active agents, depending upon the intended use.
Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions are known to those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating and compressing when necessary for tablet forms, or mixing, filling and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraural and/or rectal administration.
Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles or excipients may be employed in the pharmaceutical compositions. Illustrative solid carriers include starch, lactose, calcium sulphate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid. Illustrative liquid carriers may include syrup, peanut oil, olive oil, saline solution, and water. The carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g. solution), or a nonaqueous or aqueous liquid suspension.
A dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound (i.e., a compound of formula I or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt or solvate thereof) and preferably is made up of one or more pharmaceutical dosage units. The selected dose may be administered to a mammal, for example, a human patient, in need of treatment mediated by inhibition of matrix metalloproteinase activity, by any known method of administering the dose including topical, for example, as an ointment or cream; orally, rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural or intraocular infusion.
A xe2x80x9ctherapeutically effective amountxe2x80x9d is intended to mean that amount of a compound of formula I or II that, when administered to a mammal in need thereof, is sufficient to effect treatment for disease conditions alleviated by the inhibition of the activity of one or more matrix metalloproteinases, such as tumor growth, invasion or metastasis, osteoarthritis, rheumatoid arthritis, osteoporosis, periodontitis, gingivitis, chronic dermal wounds, corneal ulcerations, degenerative skin disorders, multiple sclerosis, stroke, diabetic retinopathy, macular degeneration, angiofibromas, hemangiomas, chronic obstructive pulmonary disease, such as emphysema, atherosclerosis, glomerular disease, cardiac arrhythmia, endometriosis or disease conditions characterized by unwanted angiogenesis. The amount of a given compound of formula I that will correspond to a xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending upon factors such as the particular compound, the disease condition and the severity thereof, and the identity of the mammal in need thereof, but can nevertheless be readily determined by one of skill in the art.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is alleviated by the inhibition of the activity of one or more matrix metalloproteinase, such as tumor growth, invasion or metastasis, osteoarthrities, rhematoid arthritis, osteoporosis, periodontis, gingivitis, chronic dermal wounds, corneal ulcerations, degenerative skin disorders, multiple sclerosis, stroke, diabetic retinophathy, macular degeneration, angiofibromas, hemangiomas, or disease conditions characterized by unwanted angiogenesis, and includes:
(a) prophalactic treatment in a mammal, particularly when the mammnal is found to be predisposed to having the disease condition but not yet diagnosed as having it;
(b) inhibiting the disease condition; and/or
(c) alleviating, in whole or in part, the disease condition.
The inventive compounds, and their salts, solvates and prodrugs, may be prepared by employing the techniques available in the art using starting materials that are readily available. Certain novel and exemplary methods of preparing the inventive compounds are described below.

The methods of preparing compounds of Formula I, where R5 is carboxyl, culminate in the deprotection of esters (1) to the corresponding carboxylates as illustrated in Reaction Scheme I below. Appropriate types of esters (1) and the cleavage of R5 are described, for example, in Greene, T; Wuts, P. G. M. xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d Wiley: 1991 and Kocienski, P. J. xe2x80x9cProtecting Groups,xe2x80x9d Thieme: 1994, which are incorporated herein by reference. Some examples and conditions encountered herein are given below. 
As an example of a typical ester cleavage, an ester of Formula (1) where R6 is benzyl is placed in a suspension with solvent, for example, ethyl acetate also containing metal catalyst, preferably palladium(0) in a hydrogen source such as hydrogen gas at one atmosphere or above, at ambient temperature for 30 minutes to three days, preferably four hours. The carboxylates of Formula I, where R5 is xe2x80x94COOH, are amenable to customary isolation and purification.
For esters of Formula (1) where R6 is t-butyl, the ester (1) is deprotected in a solution of solvent, preferably chloroform or dichloromethane, with excess trifluoroacetic acid, at ambient temperature for 15 minutes to 12 hours to obtain a carboxylate of Formula I.
For esters of Formula (1) where R6 is allyl, the ester (1) undergoes cleavage in an inert solvent, preferably acetonitrile, with a catalytic amount of palladium catalyst, such as tetrakis(triphenylphosphine)-palladium(0), with an excess of secondary amine, such as morpholine, for 15 minutes to 12 hours at ambient temperature.
Where the above conditions are incompatible with functional groups contained in either R4 or R5, other protective strategies may be used. For example, simultaneous protection where R4 is olefinic and R5 is carboxylate may occur through their connection as in a halolactone of Formula (2) where X is halogen, as displayed in Reaction Scheme II below. The halolactone (2) undergoes reductive opening to compounds of Formula I, where R4 is allyl and R5 is carboxylate. 
A solution of halolactone (2) is exposed to a reductive environment, preferably excess zinc powder in acetic acid. The resulting carboxylate of Formula I where R4 is allyl is isolated and purified via conventional methods.
Compounds (5) of Formula I where R5 is hydroxamic acid (xe2x80x94C(O)NHOH) may be obtained from compounds (3) of Formula I where R5 is carboxyl. Any of the numerous commercially available coupling reagents can be used for conversion either to a protected version of a compound of Formula (4) where R7 is alkyl or directly to hydroxamate (5), as outlined by the Reaction Scheme III below: 
Step 1xe2x80x94Preparation of Compounds of Formula (4) or (5
Carboxylic acids of Formula (3) and hydroxylamine or its O-alkyl derivatives in inert solvent, preferably dimethylformamide (DMF), are coupled with any of the numerous available coupling reagents, preferably benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP), at ambient temperature for one to 24 hours to provide either hydroxamates (5) or O-alkyl hydroxamates (4), respectively. The products are amenable to routine handling and purification.
Step 2xe2x80x94Preparation of Compounds of Formula (5) from Compounds of Formula (4)
Protected hydroxamates of Formula (4) are deprotected as determined by the nature of the protecting group R7. Where R7 is a trialkylsilyl, mild acid hydrolysis or fluoride cleavage in protic or aprotic solvent at ambient temperature or below for one to 12 hours is sufficient. Where R7 is benzyl, selective deprotection without Nxe2x80x94O bond cleavage proceeds in the presence of palladium on carbon, with a hydrogen source, such as hydrogen gas at atmospheric pressure, in a suitable solvent, such as dimethylformamide or methanol.
Pyrrole compounds of Formula II can be prepared from cyclocondensation of amines of Formula (6) with tetrahydrofurans of Formula (7), as shown below in Reaction Scheme IV: 
Condensation of amine salts of Formula (6) and 2,5-dimethoxytetrahydrofurans of Formula (7) may be carried out in acetic acid for a period of one to 24 hours at temperatures from 40xc2x0-90xc2x0 C. Another effective set of conditions includes heating a solution of compounds (6) and (7) in inert organic solvent, for example 1,2-dichloroethane, with or without acid, such as trifluoroacetic acid, and with or without stoichiometric amounts of water, for a period of one to 48 hours at 4xc2x0-90xc2x0 C. The product of Formula II is isolated and purified by conventional means.
Another method for preparation of pyrrole compounds of Formula II involves earlier ring formation. Cyclocondensation of D-amino acids of Formula (8) with tetrahydrofurans of Formula (7) and subsequent coupling is shown below in Reaction Scheme V: 
Step 1xe2x80x94Preparation of Compounds of Formula (9)
Amino acids of Formula (8) and 2,5-dimethoxytetrahydrofurans of Formula (7) are dissolved or suspended in solution in an inert organic solvent, for example 1,2-dichloroethane, with chlorotrimethylsilane, with or without acid, such as trifluoroacetic acid, and with or without a base, such as pyridine, for a period of one to 48 hours at ambient temperature to 80xc2x0 C., preferably the latter. The product (9) is isolated and purified by conventional means.
Step 2xe2x80x94Preparation of Compounds of Formula II from Compounds of Formulas (9) and (10)
Carboxylates of Formula (9) and amines of Formula (10) are coupled under typical coupling conditions. Acids of Formula (9) may first be converted to a corresponding activated ester (i.e., acid fluoride) or used with a reagent, for example BOP, along with the amine (10) in an inert solvent such as chloroform, and with or without a base such as N-methylmorpholine (NMM), for a period of one to 48 hours at 0xc2x0 C. to ambient temperature, preferably the latter. The product II is isolated and purified by conventional means.
Amines of Formula (6), where R4 is hydrogen and R5 is an ester (xe2x80x94COOR6) are available after two steps as shown in Reaction Scheme VI: coupling of commercially available D-aspartate derivatives (11) and various amines (10) of commercial or synthetic origin. Subsequent deprotection of protected amines (12) furnish amine salts (6). 
Step 1xe2x80x94Preparation of Compounds of Formula (12)
Carboxylates of Formula (11) and amines (10) are condensed as described above for the preparation of a compounds of formula II according to Reaction Scheme V. Typical coupling reagents, for example BOP, are used in an inert solvent such as chloroform, and with or without a base such as N-methylmorpholine, at 0xc2x0 C. to ambient temperature, preferably the latter, for a period of one to 48 hours to furnish the product of Formula (12), which is isolated and purified by conventional means.
Step 2xe2x80x94Preparation of Amines of Formula (6)
t-Butoxycarbonylamines of Formula (12) are deprotected traditionally, for example, in an inert solvent, preferably dichloromethane or chloroform, with an excess of trifluoroacetic acid, at 0xc2x0 C. to ambient temperature, preferably the former, for 30 minutes to 18 hours to obtain amine salts (6), which can be immediately used without further purification but are amenable to customary handling and purification.
Aspartates of Formula (8) where R4 is hydrogen are available for purchase, or from synthesis according to methods understood by those skilled in the art, such as those described in the literature. However, aspartates of Formula (8) where R4 is alkyl must be synthesized. An example of this synthesis is shown in Reaction Scheme VII below. D-Aspartate (13) is converted via diallyl ester (14) to aspartate (15), which undergoes Ireland-Claisen rearrangement of the H-ester to allyl compound (16). Appropriate processing provides carboxylates of Formula (18) where R4 is allyl, which are suitable for later conversion to lower alkyls, for example, reduction to where R4 is propyl. 
Step 1xe2x80x94Preparation of Compounds of Formula (14)
D-Aspartate dual esters can be produced in any of a variety of ways. For example, D-aspartate (13) is esterified with an excess of allyl alcohol, preferably in inert solvent such as benzene with stoichiometric amounts of acid, such as p-toluenesulfonic acid, for one to 12 hours, at reflux under conditions to azeotropically remove water. The salt (14) precipitates or is otherwise isolated and purified by conventional means.
Step 2xe2x80x94Preparation of Compounds of Formula (15)
Protection of an amine is well documented and understood by those skilled in the art. For example, amine salt (14) is treated with excess di-t-butyl-dicarbonate in appropriate solvent, preferably dichloromethane, in the presence of base, preferably triethylamine for one to 24 hours at ambient temperature. The product (15) is isolated and purified by conventional means.
Step 3xe2x80x94Preparation of Compounds of Formula (16)
Esters of Formula (15) are treated with a specified stoichiometric amount of hindered lithiun amide base, preferably two equivalents of lithium hexamethyldisilazide, in an inert aprotic solvent, preferably tetrahydrofuran, at xe2x88x9278xc2x0 C. for 15 to 45 minutes, whereupon preferably two equivalents or more of trialkylsilyl chloride, preferably chlorotrimethylsilane, are added and the reaction solution is subsequently warmed at 50 to 70xc2x0 C. or reflux for 30 minutes to 4 hours, then allowed to cool, and quenched with methanol. Subsequent routine aqueous workup leads to isolation of allyl compound (16), which is purified by conventional means.
Step 4xe2x80x94Preparation of Compounds of Formula (17)
Acids of formula (16) are esterified to distinguish carboxyl termini. This esterification can be carried out by any of a number of means understood by those skilled in the art, preferably with an appropriate isourea to prevent racemization, for example with O-benzyl-N,Nxe2x80x2-diisopropylurea, in inert solvent such as chloroform, at reflux for 3 to 6 hours. The diester (17) is isolated and purified by conventional means.
Step 5xe2x80x94Preparation of Compounds of Formula (18)
Selective mono-deprotection of diesters of Formula (17) is effected preferentially by means of routine allyl ester cleavage conditions, as discussed above for Reaction Scheme I. A solution of the diester (17) is placed in polar aprotic solvent, preferably acetonitrile, with palladium catalyst, for example with palladium (0) tetrakis-(triphenylphosphine) and excess secondary amine base, preferably morpholine at ambient temperature for 15 minutes to four hours, preferably 30 minutes. The product acid of Formula (18) is isolated and purified in routine manner.
For the simultaneous protection of R4 and R5 functionality for certain compounds of Formula I, for example where R4 is allyl and R5 is carboxyl, the halolactone-amide of Formula (2) is prepared. The synthesis of these compounds of Formula (2) uses methods described for Formula II in Reaction Scheme V, as shown in Reaction Schemes VIII and IX below.
In Reaction Scheme VIII, the monoacid (19) undergoes conventional coupling (as described for Reaction Scheme V) with amine of Formula (10) to give amide of Formula (20), which is deprotected to amine of Formula (21). The pyrrole ring is formed (as in the preparation of pyrroles in Reaction Scheme V) on amine (21) with dimethoxy-furan (7) to obtain products of Formula (2). 
Step 1xe2x80x94Preparation of Compounds of Formula (20)
The coupling of acid (19) and amine (10) is accomplished with the routine peptide amide forming conditions as described above in Reaction Scheme V, Step 2.
Step 2xe2x80x94Preparation of Compounds of Formula (21)
The deprotection of amine (20) to amine salt (21) is accomplished as described above for the preparation of amines of Formula (6) in Reaction Scheme VI, Step 2.
Step 3xe2x80x94Preparation of Compounds of Formula (2)
The formation of pyrroles of Formula (2) from (21) and (7) can be accomplished as described above in Reaction Scheme V, Step 2.
An alternate route to compounds of Formula (2) proceeds via formation of pyrrole (23) prior to a coupling, as illustrated by Reaction Scheme IX below: 
Step 1xe2x80x94Preparation of Compounds of Formula (22)
The deprotection of monoacid (19) to amine salt (22) is as described above for the preparation of amines of Formula (6) in Reaction Scheme VI, Step 2.
Step 2xe2x80x94Preparation of Compounds of Formula (23)
The condensation and cyclization of compounds (22) and (7) provides pyrroles of Formula (23) in the same manner as discussed above for Reaction Scheme V, Step 1.
Step 3xe2x80x94Alternate Preparation of Compounds of Formula (2)
The coupling of acid (23) and amine (10) is accomplished with the routine peptide amide formation conditions described above for Reaction Scheme V, Step 2.
For the preparation of late stage intermediates of Formula (2), aspartate derivatives of Formula (19) are needed. As shown in Reaction Scheme X below, intermediate (16) is alternatively cyclized to afford halolactones (25), which simultaneously protect the ultimate R5 carboxylate and olefin of R4 at an early stage. 
Step 1: Preparation of Compounds of Formula (25)
Carboxy-olefins of Formula (16) in a suspension of inert solvent, for example tetrahydrofuran or acetonitrile, and excess aqueous alkali, preferably sodium bicarbonate, are exposed to excess halogen, preferably iodine, initially at xe2x88x9210 to 0xc2x0 C., then allowed to warm and equilibrate at ambient temperature over a period of 2 to 24 hours. The product halolactone (25) is isolated and purified according to routine methods.
Step 2: Preparation of Compounds of Formula (19)
Compound (19) is prepared from compound of Formula (25) in a manner identical to that described above for the preparation of compounds of Formula (18) in Reaction Scheme VII, Step 5.
The tetrahydrofuran of Formula (7) where R1 is hydrogen and X is a single bond is commercially available. More often 3-substituted furans (26) are treated with bromine in methanol to provide 2,5-dimethoxy-dihydrofurans (27), which are in turn hydrogenated to produce tetrahydrofurans (7). The overall approach is illustrated in Reaction Scheme XI below: 
Step 1xe2x80x94Preparation of Compounds of Formula (27)
Furans of Formula (26) are treated with stoichiometric amounts of bromine in methanol as solvent or in mixtures with less polar solvents, at temperatures of xe2x88x9220xc2x0 C. to ambient temperature, preferably xe2x88x9210xc2x0 C., for 10 minutes to 8 hours, preferably for 90 minutes. The products (27) are isolated and purified by conventional means.
Step 2xe2x80x94Preparation of Compounds of Formula (7)
Olefins of Formula (27) are reduced in a suitable protic or aprotic solvent under hydrogen at one atmosphere or above in the presence of metal catalyst, preferably rhodium on alumina or palladium on carbon, in the temperature range from about 0xc2x0 C. to 40xc2x0 C., for about 1-8 hours, preferably 3 hours. Compounds (7) are isolated and purified by conventional means.
The tetrahydrofuran (7a) of Formula (7) where X is a single bond and R1 is formyl (xe2x80x94CHO) is commercially available. Construction of various X and R1 combinations are possible through elaboration upon the carboxaldehyde. One possible scenario is displayed in Reaction Scheme XII below. 
Step 1xe2x80x94Preparation of the Compound of Formula (28)
As an example, the aldehyde of Formula (7a) is added to a mixture with at least two equivalents of the reagent formed from carbon tetrabromide, triphenylphosphine, and zinc powder in dichlormethane over 24 hours at ambient temperature. After 60 minutes at ambient temperature, the desired intermediate 1,1-dibromoolefin can be isolated and purified in conventional manner. The alkyne product of Formula (28) is produced from treatment of 1,1-dibromoolefin with alkyllithium, preferably n-butyllithium, in inert, aprotic solvent, preferably tetrahydrofuran, at low temperature, xe2x88x9278xc2x0 C. to 0xc2x0 C. after 60 minutes, and subsequent capping with trialkylstannyl halide, such as chlorotributyl-tin (IV). The product (28) can be handled and purified with routine methods.
Step 2xe2x80x94Preparation of the Compounds of Formula (29)
The alkyne (28) is elaborated through an alkylation with the corresponding anion for compounds of Formula (7) where X is xe2x80x94Cxe2x89xa1Cxe2x80x94 and R1 is alkyl, or the alkyne (28) is coupled in a Stille-type reaction to a compound of Formula (7) where X is a xe2x80x94Cxe2x89xa1xe2x80x94Cxe2x80x94 and R1 is aryl. For the former compounds of Formula (29) where R1 is alkyl, a solution of the alkyne (28) in inert solvent at low temperature, ambient or below, undergoes metal exchange with a suitable alkyllithium, and is subsequently alkylated with a suitable alkylating reagent, for example primary alkyl halides. For compounds of Formula (29) where R1 is vinyl or aryl, the alkyne (28) and vinyl or aryl halide couple in the presence of palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), with aprotic solvent at below or above ambient temperature. The products of Formula (29) are isolable and can be purified by conventional techniques.
Step 3xe2x80x94Preparation of the Compounds of Formula (7b)
The alkyne (29) can be hydrogenated in suitable solvent, with a hydrogen source, such as hydrogen gas at atmospheric pressure, in the presence of a catalyst, such as palladium on carbon, to furnish, for example, compounds (7b) of Formula (7) where X is xe2x80x94CH2CH2xe2x80x94. The products of Formula (7b) can be subjected to routine handling and purification.
Other tetrahydrofurans of Formula (7) where X is a single bond and R1 is vinyl or aryl are available from the corresponding furans. The appropriately functionalized furans arise from substituent elaboration via coupling of appropriate vinyl or aryl partners: carefully choreographed sequential Suzuki, Heck, or Stille-style couplings with olefins, haloaryls, arylboronic acids, aryltriflates and/or aryltinalkyls can be used to prepare arylfurans (22), as exemplified in Reaction Schemes XIII, XIV, XV, and XVI below.
An example of a Suzuki-style coupling to develop R1 is shown below in Reaction Scheme XIII. 
3-Bromofuran (30) and boronic acids of Formula (31) where R8 is aryl or vinyl, in a mixture of inert solvent, for example benzene, and aqueous alkali, preferably sodium carbonate, in the presence of a suitable metal catalyst, are heated at 30xc2x0 to reflux temperature for one to 24 hours. Suitable metal catalysts include palladium(0) tetrakis(triphenylphosphine) or palladium(II) acetate as examples. The product (32) is isolable and can be processed in routine fashion.
Alternatively, the roles of the reaction partners can be reversed, for example as shown in Scheme XIV below wherein furan-3-yl-boronic acid (33) and unsaturated halides of Formula (34), where X is bromide, iodide, or triflate and R8 is vinyl or aryl, couple to result in compounds (32). 
Furan-3-ylboronic acid (33) and vinyl or aryl halides of Formula (34) are reacted under conditions similar to those described above for Reaction Scheme XIII.
The Heck coupling represents additional useful methodology to introduce and elaborate substituents on unsaturated systems as displayed in Reaction Scheme XV as follows: 
3-Bromofuran (30) and olefinic compounds of Formula (35) where R8 is aryl or vinyl, are placed in a suspension of inert solvent, in the presence of metal catalyst, preferably palladium(0) tetrakis(triphenylphosphine) or palladium(II) acetate with catalytic tertiary phosphine, preferably tri(o-tolyl)phosphine or tri(o-tolyl)arsine, at ambient to reflux temperature for one to 24 hours. The product (32) is isolable and can be processed in routine fashion.
For larger R1 groups, further elaboration of smaller R1 groups can be obtained from different coupling conditions, complimentary to those reactions depicted in Reaction Schemes XIII, XIV, and XV above. For example, once the above methods are used to prepare a furan of Formula (36), it can in turn be manipulated to join an additional vinyl or aryl group as shown in Reaction Scheme XVI below: 
Step 1: Preparation of Compounds of Formula (37)
Phenol of Formula (36) in a solution of inert solvent, for example chloroform, in the presence of amine base, preferably 2,6-lutidine, at a temperature of xe2x88x9210xc2x0 C. or above, preferably 0xc2x0 C., is treated with a stoichiometric amount of trifluoromethanesulfonic anhydride. The product triflate (37) is potentially reactive; it may be isolated and purified under anhydrous conditions in inert atmosphere, and should be used quickly.
Step 2: Alternate Preparation of Compounds of Formula (32b)
Either triflate of Formula (37) or vinyl halide of Formula (37a) is coupled with trialkylvinyl or aryl tin(IV) of Formula (38) in a solution of inert solvent, such as benzene,in the presence of metal catalyst, such as palladium(II) acetate, with a stoichiometric amount of lithium chloride at ambient temperature or above. The coupled product (32b) is amenable to conventional isolation and purification.
The furan building components in Reaction Schemes XIII, XIV, XV, and XVI are readily available. 3-Bromofuran (30) can be purchased from Aldrich. Furan-3-yl-boronic acid can be prepared, for example, as described in Thompson, W. J.; Gaudino, G. J. Org. Chem. 1984, 49, 5237-5243. Furans of Formula (36) can be synthesized using the methodology outlined above for Reaction Schemes XIII, XIV, XV, and XVI. Boronic acids of Formula (31) are known in the literature or can be synthesized. Organotin(IV) compounds of Formula (38) are also known in the literature or can be synthesized.
All compounds of Formulas III, IV, V, VI, VII, and VIII where R5 is carboxyl can be produced from the corresponding esters as described, above for Formula I in Reaction Scheme I. Compounds of Formulas III, IV, V, VI, VII, and VIII where R5, is N-hydroxycarbamoyl (xe2x80x94C(O)NHOH) can be produced by the method described above for Reaction Scheme II.
The heterocyclic acetic acid derivatives of Formula (40) where R9 is alkoxy, alkylamino, or oxazolidin-3-yl, are alkylated with xcex1-haloesters of Formula (39) where X is chloride, bromide, iodide, or triflate to target esters of Formula (41) as shown below in Reaction Scheme XVII. The R9 group of compounds of Formula (40) can serve as a chiral auxiliary to help establish the absolute stereochemistry of compounds of Formula (41). 
Solutions of compounds of Formula (40) in inert solvent, preferably tetrahydrofuran, are added to solutions with stoichiometric and/or defined amounts of a suitable base, for example, sodium hexamethyldisilazane or lithium diisopropylamide, in inert solvent, preferably tetrahydrofuran, at low temperature, preferably xe2x88x9278 to xe2x88x9215xc2x0 C., for five minutes to one hour, are suitable to effect formation of the corresponding anion. Then xcex1-haloesters of Formula (39) are added alone or in a solution of inert solvent. The cold reaction mixture is allowed to stir for 30 minutes to 24 hours, preferably one hour, to form target esters (41), which are isolated and purified by routine methods.
For an example of the alkylation process outlined by Reaction Scheme XVII where R9 is a chiral auxiliary, see Reaction Scheme XVIII below. According to this scheme, amides of Formula (40) where R9 are chiral oxazolidines (see Formula (42) below) can undergo stereoselective alkylation to provide products of Formula (43), which in turn can furnish hydroxyethylamides of Formula (44) (Formula I where R5 is an ester, Y is xe2x80x94CH(OH)xe2x80x94). 
Step 1xe2x80x94Preparation of Compounds of Formula (43)
Compounds of Formula (43) are prepared from compounds of Formula (40) where R9 is a chiral oxazolidine under conditions identical to those described above for the preparation of compounds of Formula (41) from compounds of Formulas (39) and (40) in Reaction Scheme XVII, except with compounds of Formula (42) substituted for compounds of Formula (40). The product of Formula (43) is amenable to conventional isolation and purification.
Step 2xe2x80x94Preparation of Compounds of Formula (44)
Compounds of Formula (43) in solvent, such as tetrahydrofuran, is treated with excess acid, preferably dilute, 0.5 molar aqueous hydrochloric acid, at ambient to reflux temperature, preferably the former. The product of Formula (44) is isolated and purified via routine methods.
The disubstituted heterocycles of Formula (41) may also be assembled in a variation in the order of execution shown above in Reaction Scheme XVIII. The alkylations in the above Schemes XVII and XVIII can precede the installation or elaboration of the portion that contains X and R1. Late stages use appropriate sequences of coupling methods discussed in Reaction Schemes XIII, XIV, XV, and XVI. For example, in Reaction Scheme XIX below, monosubstituted heterocycle of Formula (46) might be halogenated to an appropriately disubstituted heterocycle of Formula (47), which in turn is a coupling partner for methodology outlined in Reaction Schemes XIII, XIV, XV, and XVI. In this example, a Suzuki coupling with boronic acid of Formula (31) is used to give a compound of Formula (48). 
xcex1-Haloesters of Formula (39) where R4 is hydrogen are commercially available. When R4 is alkyl, many compounds of Formula (39) can be prepared by syntheses described in literature. For example, many amino acids can be converted to optically active compounds of Formula (39) where R4 is alkyl as described in Coppola, G. M., Schuster, H. F. Asymmetric Synthesis: Construction of chiral molecules using amino acids; J. Wiley and Sons: New York, 1987.
Certain heterocyclic acetic acid derivatives of Formula (40) are commercially available in certain cases (for example, 2- or 3-thiophene acetic acid), but usually must be synthesized in various ways, as described below.
Direct alkylation on the nitrogen of an appropriate heterocycle of Formula (49), where T, U, and V are each independently carbon or nitrogen, by the xcex1-haloacetic acid derivatives of Formula (50), where X is halogen or triflate, produces the desired intermediates of Formula (51), as shown in Reaction Scheme XX below: 
Step 1xe2x80x94Preparation of Compounds of Formula (51)
Nitrogen-containing heterocycles of Formula (49) (for example, pyrazole) are placed in aprotic solvent such as N,N-dimethylformamide, and if warranted, deprotonated with a base such as sodium hydride and treated with xcex1-haloacetamides of Formula (50) where X is halogen or triflate, at room temperature or above for one to 24 hours. The products of Formula (51) are amenable to routine techniques for isolation and purification.
An analogous straightforward substitution of the heterocyclic ring involves the alkylation of an organometallic derivative of Formula (53) where M is, for example, lithium, magnesium, or copper, with an xcex1-haloacetic acid derivative of Formula (50), as shown in Reaction Scheme XXI below: 
Step 1xe2x80x94Preparation of Compounds of Formula (53)
Heterocyclic metallo derivatives of Formula (53) are available in customary fashion from a heterocycle of Formula (52). Principal methods include deprotonation of parent of Formula (52) where W is hydrogen, or from halogen-metal exchange of the corresponding halo-heterocycle of Formula (52) where W is halogen. These reactions are typically carried out in inert, aprotic solvent such as tetrahydrofuran, at ambient temperature or below, in 15 minutes to 24 hours. The organometallics of Formula (53) are typically unstable to atmosphere and moisture. They are routinely formed in situ and used immediately without isolation.
Step 2xe2x80x94Alternate Preparation of Compounds of Formula (40)
The organometallics of Formula (53) are alkylated by stoichiometric or excess amounts of acetate or acetamide of Formula (50) in inert solvent, preferably tetrahydrofuran, at low temperatures of xe2x88x9278 to 0xc2x0 C., in ten to 90 minutes. The product of Formula (40) is isolated and purified with routine methods.
As another alternative, an acylation can be carried out with oxalates or oxamates of Formula (54) where R10 is, for example, halogen, alkoxy, or imidazol-1-yl, to ketoesters or ketoamides of Formula (55), which are subsequently deoxygenated in several steps to ester or amides of Formula (40), as shown in Reaction Scheme XXII below. 
Step 1xe2x80x94Preparation of Compounds of Formula (55)
Heterocyclic organometallic derivatives of Formula (53) where M is lithium can be prepared as shown in Reaction Scheme XXI above and acylated by an oxalate or oxamate of Formula (54) where R10 is typically halogen, alkoxy, or imidazol-1-yl in inert solvent, preferably tetrahydrofuran, at low temperatures of xe2x88x9278 to 0xc2x0 C., in ten to 90 minutes. The product of Formula (55) is isolated and purified with routine methods.
Step 2xe2x80x94Preparation of Compounds of Formula (56)
The ketoester or amide of Formula (55) in solvent, preferably ethanol, at temperatures of xe2x88x9215 to 0xc2x0 C., is treated with hydride reducing agent, preferably sodium borohydride, for five minutes to four hours to provide products of Formula (56), which are isolable and purified with conventional techniques.
Step 3xe2x80x94Preparation of Compounds of Formula (57)
Alcohols of Formula (56) can be processed for deoxygenation by conversion to various moieties designated Q, preferably where Q is an ester or halide. Typically they are acylated in aprotic solution, for example chloroform, with excess acylating agent, for example acetic anhydride or acetyl chloride in the presence of excess amine base, preferably pyridine, with or without catalytic amounts of (4-dimethylamino)pyridine to give acetates of Formula (57) where Q is acetoxy, which are handled and purified in usual fashion.
Step 4xe2x80x94Preparation of Compounds of Formula (40)
xcex1-Halides or acetates of Formula (57) where Q is halogen or acetoxy, respectively, are reduced to products of Formula (40) with a metal catalyst, preferably palladium on carbon, and a source of hydrogen, preferably ammonium formate. The products (40) are handled and purified in customary manner.
The disubstituted heterocycles of Formula (40) can also be constructed in a differently ordered sequence: late formation of the portion that contains X and R1 utilizing appropriate sequences of coupling methods discussed in Reaction Schemes XIII, XIV, XV, and XVI.
Many of the monosubstituted heterocycles that are commercially available bear only one carbon in the substituent, and additional processing is necessary to prepare disubstituted heterocycles of Formula (40), as shown in Reaction Scheme XXII below. Commercially available mono-substituted heterocycles of Formula (58) where R11 is hydrogen, hydroxy, or alkoxy (for example, 3-furan carboxaldehyde or 3-furfural, where R11 is hydrogen) can be homologated through any of numerous suitable methods known to those skilled in the art, for example, that described in Martin, S. F. Synthesis 1979, 633-665, to furnish 2-heterocyclic acetic acid derivatives (59), which can be further substituted, for example as a halide of Formula (60). Alternatively, the heterocycles Formula (58) are substituted as halides of Formula (61), then homologated to derivatives of Formula (60). Subsequent linkage of a compound of Formula (60) with an appropriate coupling partner such as a compound of Formula (31) gives esters or amides of Formula (62). As recognized by those skilled in the art, the versatility of the methods in Reaction Scheme XXIII allows interchangability of the steps. For example, the substitution of halides of Formula (61) with boronic acids of Formula (31) may precede a homologation to desired intermediates of Formula (62) (not shown). 
Step 1xe2x80x94Preparations of Compounds of Formulas (59) and (60)
The heterocycles of Formulas (58) and (61) are homologated to compounds of Formulas (59) and (60), respectively, depending upon the nature of R11 and R9. See, for example, Martin, S. F. Synthesis 1979, 633-665. As an example, for compounds (58) and (61) when R11 is hydrogen, the anion of 2-trimethylsilyl-1,3-dithiane is used in inert aprotic solvent, preferably tetrahydrofuran at low temperature, 0xc2x0 to xe2x88x9278xc2x0 C. for 30 minutes to several hours, to obtain the corresponding dithiane adduct, which is subsequently converted through any of a variety of methods to derivatives of Formula (59). An example of dithiane removal uses mercuric chloride in water and alcohol to afford an ester of Formula (59) where R9 is alkoxy. The products of Formula (59) are amenable to conventional handling and purification.
Step 2xe2x80x94Preparations of Compounds of Formulas (60) and (61)
As an example of the introduction of the second heteroaromatic substituents, compounds of Formulas (59) and (58) in an inert solvent are halogenated, for example, with a bromine source, such as bromine or N-bromosuccinimide, at ambient temperature or below, for an hour to a day. The resultant hetereoaryl halides of Formulas (60) and (61), respectively, are subject to routine purification and manipulation.
Step 3xe2x80x94Preparations of Compounds of Formula (62)
The coupling of heteroaryls of Formula (60) are carried out analogous to that described for Reaction Schemes XIII, XV, or XVI to obtain compounds of Formula (62).
Amides with the generic Formula (40) where R9 is alkylamino are often available from the corresponding carboxylic acid or activated esters of Formula (40) where R9 is alkoxy or hydroxy, as exemplified in Reaction Scheme XXIV below: 
The formation of amides (64) (i.e., Formula (40) where R9 is alkylamine) results from acids of Formula (63) coupling with amines of Formula (10) under the same conditions as described above for Reaction Scheme V, Step 2. The products of Formula (64) are isolated and purified by conventional methods.
Oxazolidines of Formula (42) can be made from the acetamides of Formula (65) where Y in terms of formula I is xe2x80x94CH(OH)xe2x80x94, as shown in Reaction Scheme XXV below: 
The hydroxyamides of Formula (65) are placed in solution containing acetone or its equivalent, preferably 2-methoxypropene, with a catalytic amount of acid, such as p-toluenesulfonic acid, under dehydrating conditions, such as trapping of water with a Dean-Stark apparatus, at ambient temperature to reflux, for a suitable amount of time to convert starting material (65). The product (42) is amenable to routine processing for isolation and purification.
A preferable avenue to oxazolidines of Formula (42) involves coupling of oxazolidines of Formula (67) to acetic acids of Formula (63), as shown in Reaction Scheme XXVI below. The oxazolidines (67) in turn originate from amino-alcohols of Formula (66) of commercial and synthetic origin. 
Step 1xe2x80x94Preparation of Compounds of Formula (67)
Compounds of Formula (67) are prepared from compounds of Formula (66) using a method similar to that described above for the preparation of compounds of Formula (42) Reaction Scheme XXV, except lower temperatures are preferred. The products of Formula (67) can be somewhat unstable and are routinely used in situ or immediately in the next reaction without purification.
Step 2xe2x80x94Alternative Preparation of Compounds of Formula (42)
Conditions for the formation of amides with typical coupling reagents as discussed above for Reaction Scheme V, Step 2, apply to the preparation of compounds of Formula (42).
For mono-substituted heterocycles that are not available commercially, the rings may be constructed. For example, for the compounds of Formula III, as shown below in Reaction Scheme XXVII, tetrahydrofurans of Formula (68) where R12 is hydrogen or alkyl are condensed with amines of Formula (69) to provide pyrroles of Formula (70). Depending on the nature of X and R1, R12 of pyrrole (70) may be converted from hydrogen to a halogen and subsequently an alkyl (as in Reaction Scheme XXII, for example). 
Compounds of Formula (70) can be prepared from compounds of Formulas (68) and (69) using the conditions identical to those described for the preparation of pyrroles of Formula II in Reaction Scheme IV.